The overall goals of this project are to characterize the determinants of vascular structure and function, and evaluate their effects on cardiovascular morbidity and mortality 1. Increased aortic pulse wave velocity (aPWV) has been associated with mortality in clinical but not general populations. Aortic PWV was measured at baseline in 2488 older adults. Over an average of 4.6 years of follow-up, 265 deaths occurred with 111 categorized as cardiovascular in cause. Higher aortic aPWV quartile was associated with both total mortality (P = 0.010) and CV mortality (P=.006), independent of age, gender, race, SBP, known CV disease, creatinine, cholesterol and smoking. Thus, among a generally healthy, well-functioning, community dwelling population, aPWV, a marker of arterial stiffness, is associated with higher total mortality and CV mortality specifically. 2. In order to investigate the hypothesis that the age-associated changes in cardiovascular structure and function represent the mechanism through which increased age exerts its deleterious effects on cardiovascular morbidity and mortality, and to test the related hypothesis that physiologic vascular properties explain the chronologic age-associated increased risk of atherosclerosis, we plan to evaluate traditional as well as novel measures of vascular properties, and examine how they relate to non-invasive assessments of atherosclerosis. This will be performed in 300 BLSA subjects as well as individuals with known absence of coronary artery disease and patients with known premature coronary artery disease. A research and development contract has been awarded to procure novel non-invasive imaging tools such as electron beam computed tomography, vascular magnetic resonance imaging, and vascular magnetic resonance angiography (Project Officer, S. Najjar). 3. Isolated systolic hypertension (ISH) is the dominant form of hypertension in older individuals, and is associated with a significant increase in cardiovascular morbidity and mortality. But the factors underlying the increased risk of ISH have not been fully elucidated. Since alterations in vascular structure and function are increasingly recognized as potent predictors of adverse events, we investigated the cardiovascular changes associated with ISH. 447 Taiwanese subjects over the age of 50 and with DBP<90 mmHg, were classified into a normotensive group (NT, SBP<140 mmHg) and an untreated ISH group (SBP>140 mmHg). The NT group was on average 5 years younger than the ISH (62+/-8 and 67+/-7 years, p<0.05). As expected SBP and PP were significantly higher in the ISH group. Furthermore, we found that a number of vascular structural and functional parameters were significantly greater in the ISH group than in the NT group. Thus, ISH is not isolated , but rather is associated with accelerated alterations in a host of cardiovascular structural and functional parameters. The increased risk associated with ISH may, in part, be mediated through these alterations, some of which have already been established as risk factors for cardiovascular diseases independent of blood pressure. 4. Hypertension (HTN) is generally considered a risk factor for arterial stiffening because chronically increased blood pressure determines structural and functional changes in arterial walls. However, arterial stiffening may also predispose to the development of HTN. We therefore evaluated whether arterial stiffening predicts the development of HTN in normotensive healthy adults. Pulse wave velocity (PWV), a non-invasive index of arterial stiffness, was measured in 364 volunteers from the Baltimore Longitudinal Study of Aging who were normotensive at baseline. After a mean follow-up of 5.1+/-2.9 years, 75 subjects (21%) developed HTN. Variables that were significantly associated with the development of HTN included older age, higher PWV, body mass index, systolic blood pressure, diastolic blood pressurre, and triglycerides, and lower HDL cholesterol. Beacuse of a significant interaction between age and PWV, we examined younger (age<50 years) and older age groups separately. We found that in healthy normotemsive younger, but not older, adults, higher arterial stiffness is an independent predictor of future HTN. Thus, screening for arterial stiffening may identify a subset of normotenisve younger individuals at increased risk for developing HTN, in whom early interventions may be indicated. 5. Intimal medial thickness (IMT) and vascular stiffness have been shown to be independent predictors of adverse cardiovascular events. The metabolic syndrome (MS) is defined as the clustering of 3 or more of the cardiovascular risk factors of dysglycemia, hypertension, dyslipidemia, and obesity. We evaluated whether the clustering of multiple components of the MS has a greater impact on these vascular parameters than individual components of the MS in 471 participants from the Baltimore Longitudinal Study on Aging who were without clinical cardiovascular disease and not on antihypertensive therapy. MS was an independent predictor of increased carotid IMT and stiffness, and conferred a disproportionate increase in carotid IMT (16%) and stiffness (32%,) compared to controls even after taking into account each individual component of the MS. This suggests that the components of the MS interact to synergistically impact vascular thickness and stiffness. Future studies should examine whether the excess cardiovascular risk associated with the MS is, in part, mediated through the amplified alterations in these vascular properties (J Am Coll Cardiol. 2004;43(8):1388-95).